Method and device for the delivery of a substance including a covering

ABSTRACT

An abrasion device and method for delivery of substances into the skin using a microabrader for delivering a substance into the skin are disclosed. An abrasion device with a cover is also disclosed. Such devices and methods can be effectively used to deliver bioactive substances into skin.

FIELD OF THE INVENTION

The present invention relates to a method and device for abrading theskin.

BACKGROUND OF THE INVENTION

Delivery of substances to the body through the skin has typically beeninvasive, involving needles and syringes to facilitate intradermal (ID),intramuscular (IM) or subcutaneous (SC) injection. These methods may bepainful for the subject, require the skills of a trained practitionerand often produce bleeding. There have been efforts to overcome thesedisadvantages by use of devices, which abrade the stratum corneum, thethin external layer of keratinized cells about 10-20 μm thick. Thebioactive substance is delivered to the exposed viable epidermis.

This technique avoids the nerve net and deposits the bioactive substancein close proximity to blood vessels and lymphatics for absorption anddelivery of the substance throughout the body.

For topical delivery of vaccines, the epidermis itself is a particularlydesirable target as it is rich in antigen presenting cells. Incomparison, the dermal layer below the epidermis contains fewerantigen-presenting cells. Furthermore, the stratum corneum and epidermisdo not contain nerves or blood vessels, so this method has the advantageof being essentially painless and blood-free while giving access to theskin layers capable of responding to the antigen.

A variety of devices and methods purport to disrupt the stratum corneumfor the purpose of delivering substances to the body. For example,breach of the stratum corneum may be achieved by puncturing as taught inU.S. Pat. No. 5,679,647 to Carson, et al. This patent teaches thatnarrow diameter tines, such as those found on devices used fortuberculin skin tests and allergy tests, can be coated withpolynucleotides or oligonucleotides and used for delivery of suchmaterials into the skin. The method of using such devices involvespuncturing the skin with the tines resulting in intracutaneous injectionof the coated substance.

U.S. Pat. No. 5,003,987; U.S. Pat. No. 5,879,326; and U.S. Pat. No.3,964,482 teach breaching the stratum corneum by cutting.

SUMMARY OF THE INVENTION

The present invention is directed to a method and device for abradingthe skin, and particularly, the stratum corneum of the skin.

Substances to be delivered particularly include bioactive substances,including pharmaceutical agents, medicaments, vaccines and the like.Substances may be in solid or liquid form, depending on formulation anddelivery method. They can be delivered, inter alia, in the form of drypowders, gels, solutions, suspensions, and creams. Suitable formulationsare familiar to those of skill in the art. Particularly preferredmedicaments for delivery by the methods of the invention includevaccines, allergens and gene therapeutic agents.

One aspect of the invention is directed to a method and device forpreparing a delivery site on the skin to enhance the delivery of apharmaceutical agent through the stratum corneum of the skin to asufficient depth where the pharmaceutical agent can be absorbed andutilized by the body.

Dermal tissue represents an attractive target site for delivery ofvaccines and gene therapeutic agents. In the case of vaccines (bothgenetic and conventional), the skin is an attractive delivery site dueto the high concentration of antigen presenting cells (APC) and APCprecursors found within this tissue, especially the epidermalLangerhan's cells (LC). Several gene therapeutic agents are designed forthe treatment of skin disorders, skin diseases and skin cancer. In suchcases, direct delivery of the therapeutic agent to the affected skintissue is desirable. In addition, skin cells are an attractive targetfor gene therapeutic agents, of which the encoded protein or proteinsare active at sites distant from the skin. In such cases, skin cells(e.g., keratinocytes) can function as “bioreactors” producing atherapeutic protein which can be rapidly absorbed into the systemiccirculation via the papillary dermis. In other cases, direct access ofthe vaccine or therapeutic agent to the systemic circulation isdesirable for the treatment of disorders distant from the skin. In suchcases, systemic distribution can be accomplished through the papillarydermis.

Aspects of the present invention provides a method and microabraderdevice to abrade the skin in conjunction with the delivery of abioactive substance, including but not limited to nucleic acids, aminoacids, amino acid derivatives, peptides or polypeptides. It has beendiscovered that nucleic acids exhibit enhanced gene expression andproduce an enhanced immune response to the expressed protein when theyare delivered simultaneously with abrasion of the stratum corneum.Similarly, allergens delivered simultaneously with abrasion produce amore vigorous immune response than conventional allergen testing methodsprovide.

In one aspect of the present invention, a microabrader is provided fordelivering a substance into the skin. Typically, the microabrader has abase with an abrading face, to which an abrading surface that iscomposed of an arrangement of microprotrusions that have at least onescraping edge. A handle attachment may or may not be present on themicroabrader, to which a handle or other grasping device is attached,mounted, or integral with. By “abrading surface” is meant the surfacethat is presented to the skin during the process of abrasion, includingmicroprotrusions, surface area between them and surrounding surface.

Other aspects of the present invention involve methods for delivering asubstance to the skin comprising the movement of the microabrader deviceacross a predetermined area of the skin to produce furrows of sufficientdepth to allow the substance, which is administered prior to,simultaneously with, or following the abrasion of the skin, to be takenup by the predetermined skin layer. By means of a microabrader device,multiple passes of the device across the skin can result inprogressively deeper furrows in the skin, thereby allowing delivery of asubstance to a desired depth with in the skin. Another aspect of theinvention is a method of using a covering for use in conjunction withthe microabrader device. Another aspect of the invention is a method ofusing a skin covering for use in conjunction with the microabraderdevice prior to abrasion. Another aspect of the invention is a method ofusing a skin covering which defines a predetermined surface area for usein conjunction with the microabrader device prior to and duringabrasion.

In accord with another aspect of the invention, a device is providedhaving a plurality of microneedles for penetrating the stratum corneumand an outer adhesive patch for adhesively attaching the apparatus tothe skin of a patient is provided, which includes an active drugdelivery means.

DESCRIPTION OF THE DRAWINGS

Embodiments of the invention are explained greater detail by way of thedrawing, where like numerals refer like elements, and wherein:

FIG. 1A and FIG. 1B are a schematic perspective view of an apparatus forcovering an abraded portion of skin of the invention;

FIG. 2 is a schematic cross section of the apparatus of FIG. 1A;

FIG. 3 is a schematic cross section of an alternate embodiment of theinvention, in the same view as FIG. 2;

FIG. 4 is a schematic cross section of an alternated embodiment of theinvention in the same view as FIG. 2;

FIG. 5 is a top view of kit of the invention;

FIG. 6 is a top view of a patient's skin with an apparatus according toone embodiment the invention applied to the skin;

FIG. 7A and FIG. 7B are a schematic cross sectional view of an alternateembodiment of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to devices and to methods for abradingthe stratum corneum to enhance the administering of a substance throughthe stratum corneum of the skin of a patient.

In certain applications, substances may be delivered using themicroabraders and methods of the invention. These substances includeAlpha-1 anti-trypsin, Anti-Angiogenesis agents, Antisense, butorphanol,Calcitonin and analogs, Ceredase, chemokines, chemoattractants,chemokinetic agents, COX-II inhibitors, dermatological agents,dihydroergotamine, Dopamine agonists and antagonists, Enkephalins andother opioid peptides, Epidermal growth factors, Erythropoietin andanalogs, Follicle stimulating hormone, G-CSF, Glucagon, GM-CSF,granisetron, Growth hormone and analogs (including growth hormonereleasing hormone), Growth hormone antagonists, Hirudin and Hirudinanalogs such as hirulog, IgE suppressors, Insulin, insulinotropin andanalogs, Insulin-like growth factors, Interferons, Interleukins,Luteinizing hormone, Luteinizing hormone releasing hormone and analogs,Low molecular weight heparin, M-CSF, metoclopramide, Midazolam,Monoclonal antibodies, Narcotic analgesics, nicotine, Non-steroidanti-inflammatory agents, Oligosaccharides, ondansetron, Parathyroidhormone and analogs, Parathyroid hormone antagonists, Prostaglandinantagonists, Prostaglandins, Receptor agonists and antagonists,Recombinant soluble receptors, scopolamine, Serotonin agonists andantagonists, Sildenafil, Terbutaline, Thrombolytics, Tissue plasminogenactivators, TNFα, and TNFα antagonist, vaccines, with or withoutcarriers/adjuvants, including prophylactic and therapeutic antigens(including but not limited to subunit protein, peptide andpolysacchraride, polysaccharide conjugates, toxoids, genetic basedvaccines, live attenuated, reassortant, inactivated, whole cells,viruses, bacteria, viral and bacterial vectors including but not limitedto those derived from adenoviruses, retroviruses and alphaviruses) inconnection with, addiction, arthritis, cholera, cocaine addiction,diphtheria, tetanus, HIB, Lyme disease, meningococcus, measles, mumps,rubella, varicella, yellow fever, Respiratory syncytial virus, tickborne Japanese encephalitis, pneumococcus, streptococcus, typhoid,influenza, hepatitis, including hepatitis A, B, C and E, otitis media,rabies, polio, HIV, parainfluenza, rotavirus, Epstein Barr Virus, CMV,chlamydia, non-typeable haemophilus, moraxella catarrhalis, humanpapilloma virus, tuberculosis including BCG, gonorrhea, asthma,atherosclerosis, malaria, E-coli, Alzheimer's Disease, H. Pylori,salmonella, diabetes, cancer, herpes simplex, human papilloma and likeother substances include all of the major therapeutics such as agentsfor the common cold, Anti-addiction, anti-allergy, anti-emetics,anti-obesity, antiosteoporeteic, anti-infectives, analgesics,anesthetics, anorexics, antiarthritics, antiasthmatic agents,anticonvulsants, anti-depressants, antidiabetic agents, antihistamines,anti-inflammatory agents, antimigraine preparations, antimotion sicknesspreparations, antinauseants, antineoplastics, antiparkinsonism drugs,antipruritics, antipsychotics, antipyretics, anticholinergics,benzodiazepine antagonists, vasodilators, including general, coronary,peripheral and cerebral, bone stimulating agents, central nervous systemstimulants, hormones, hypnotics, immunosuppressives, muscle relaxants,parasympatholytics, parasympathomimetrics, prostaglandins, proteins,peptides, polypeptides and other macromolecules, psychostimulants,sedatives, sexual hypofunction and tranquilizers and major diagnosticssuch as tuberculin and other hypersensitivity agents.

For certain applications, particularly desirable substances that can bedelivered using the microabraders and methods of the invention includedrugs, vaccines, cell-based therapeutics and prophylactics, nucleic acidderived entities and gene therapeutics, and the like used in theprevention, diagnosis, alleviation, treatment, or cure of disease.

The devices and methods of the present invention are particularlysuitable for delivery of a broad range of vaccines made by a variety ofmethods, including live attenuated bacterial and viral vaccines, killedbacterial and viral vaccines, genetically engineered vaccines, peptide,polypeptide, protein and nucleic acid vaccines. Suitable vaccinesinclude smallpox (e.g., live, viral, based on vaccinia virus strain),Japanese (mosquito borne) encephalitis (e.g., ChimeriVax™-JE); yellowfever (e.g., Arilvax®, live attenuated) Dengue (mosquito borne, e.g.,ChimeriVax™-Dengue), West Nile encephalitis (e.g., ChimeriVax™-WestNile), Hepatitis C, typhoid (e.g., HolaVax-typhoid, live attenuatedbacterial vaccine), enterotoxigenic E. Coli (traveler's diarrhea, e.g.HolaVax-ETEC), Campylobacter, H. pylori, C. difficile (active andpassive vaccines), measles (e.g., AttenuVax™, Moraten™, Morbilvax™,Rimevax™, and Rouvax™).

As used herein, the term “abrade” refers to removing at least a portionof the stratum corneum to increase the permeability of the skin withoutcausing excessive skin irritation or compromising the skin's barrier toinfectious agents. The term “abrasion” as used herein refers todisruption of the outer layers of the skin, for example by scraping orrubbing, resulting in an area of disrupted stratum corneum. This is incontrast to “puncturing” which produces discrete holes through thestratum corneum with areas of undisrupted stratum corneum between theholes.

The microabrader of certain aspects of the invention is a device capableof abrading the skin to attain this result. In implementations ofaspects of the instant invention, the device is capable of abrading theskin thereby penetrating the stratum corneum without piercing thestratum corneum. In one aspect of the invention, the microabrader alsoincludes an effective amount of a substance to be delivered. This may beincluded, for example, in a reservoir that is an integral or detachablepart of the microabrader, or may be coated on the delivery surface ofthe microabrader. By an “effective amount” of a substance is intended tomean an amount that will elicit a desired response in a subject,including, but not limited to, an immunostimulatory or immunomodulatoryresponse in the case of an allergen or vaccine, or another therapeuticor diagnostic response.

As used herein, “penetrating” refers to entering the stratum corneumwithout passing completely through the stratum corneum and entering intothe adjacent layers. This is not to say that that the stratum corneumcannot be completely penetrated to reveal the interface of theunderlying layer of the skin. Piercing, on the other hand, refers topassing through the stratum corneum completely and entering into theadjacent layers below the stratum corneum.

In certain situations, the microabrader device of certain aspects of theinvention is believed to have a unique immunological advantage in thedelivery of vaccines with the potential of increasing the vaccine'sclinical value. The penetration of the multiple microprotrusions intothe stratum corneum is suggested as having an adjuvant-like stimulatoryeffect. The “penetration” response from the multiple microprotrusion isbelieved more than a simple acute inflammatory response. These“penetration” effects can cause damage to a variety of cells andcellular architecture, causing the appearance of polymorphonuclearneutrophils (PMN) and macrophages as well as the release of IL1, tumornecrosis factor (TNF) and other agents, which can lead to a number ofother immunological responses. The soluble stimulatory factors influencethe proliferation of lymphocytes and are central to the immune responseto vaccines. In addition, these factors influence the migration andactivation of resident antigen presenting cells including Langerhan'scells and dendritic cells. The microabrader of the present invention isvaluable in promoting significant immune response to a vaccine in theabraded area. The small grooves and furrows created by themicroprotrusion array over the abraded area are believed to increase theavailability of the vaccine antigen for interaction withantigen-presenting cells compared to a vaccine applied topically in theabsence of abrasion or administered using standard needles.

The primary barrier properties of the skin including the resistance todelivery of drugs, vaccines and gene therapeutic agents reside in theoutermost layer of the epidermis, referred to as the stratum corneum.The inner layers of the epidermis generally include three layers,commonly identified as the stratum granulosum, the stratum malpighii,and the stratum germ inativum. Although not intending to be bound by aparticular mechanism of action, it is theorized that once certain drugsor other substances appear below the stratum corneum, there is littleresistance for diffusion into subsequent layers of the skin and eventualuptake by cells or absorption by the body through the bloodstream orlymphatic drainage.

Helping a substance to pass through the stratum corneum can be aneffective method for facilitating absorption of some substances, andparticularly some vaccines, by the body. The present invention isprimarily directed to a device and method for facilitating delivery of asubstance, and particularly a bioactive substance or pharmaceuticalagent, into or through the stratum corneum for more rapid absorption oflarger quantities of the bioactive substance or pharmaceutical agent bythe patient.

In certain applications of the invention, the microabrader device of theinvention penetrates, but does not pierce, the stratum corneum. Thesubstance to be administered using the methods of this invention may beapplied to the skin prior to abrading, simultaneous with abrading, orpost-abrading. According to one aspect of the methods of the invention,however, certain or specific bioactive substances, including nucleicacids, allergens and live viral vaccines are applied to the skin priorto or simultaneously with abrasion rather than being applied topreviously abraded skin. It is believed that delivery of certainsubstances, such as nucleic acids, allergens and live viral vaccines areimproved when such substances are abraded into the skin rather thanbeing passively applied to skin, which has been previously abraded. Inanother aspect of the method of the invention, however, certain orspecific bioactive substances, including virus-like particles andsubunit proteins, are believed to have improved delivery when suchsubstances are applied to pre-abraded skin. In other aspects of themethod of the invention, however, certain or specific bioactivesubstances, including whole inactivated or killed viruses, are believedto display similar efficacy whether applied to skin following abrasionor simultaneously with abrasion.

The substance may be delivered into the skin in any pharmaceuticallyacceptable form. In one aspect of the invention, the substance isapplied to the skin and an abrading device is then moved or rubbedreciprocally over the skin and the substance. It is desirable that theminimum amount of abrasion to produce the desired result be used.Determination of the appropriate amount of abrasion for a selectedsubstance is within the ordinary skill in the art. In another aspect ofthe invention, the substance may be applied in dry form to the abradingsurface of the delivery device prior to application. In this embodiment,a reconstituting liquid is applied to the skin at the delivery site andthe substance-coated abrading device is applied to the skin at the siteof the reconstituting liquid. It is then moved or rubbed reciprocallyover the skin so that the substance becomes dissolved in thereconstituting liquid on the surface of the skin and is deliveredsimultaneously with abrasion. Alternatively, a reconstituting liquid maybe contained in the abrading device and released to dissolve thesubstance as the device is applied to the skin for abrasion. It has beenfound that certain substances, such as nucleic acid preparations, mayalso be coated on the abrading device in the form of a gel.

Any device known in the art for disruption of the stratum corneum byabrasion can be used in certain methods of the invention, this includesdevices which may pierce the stratum corneum and beyond. These includefor example, microelectromechanical (MEMS) devices with arrays of shortmicroneedles or microprotrusions, sandpaper-like devices, scrapers andthe like. If the abrading device does not include a reservoir forcontainment and discharge of fluids from the device, thesubstance-containing liquid or the reconstituting liquid must beseparately applied to the skin prior to or after abrading, for examplefrom a separate dispenser or pump. However, reservoirs may be anintegral part of the abrading device. It would be desirable to have thereservoir in fluid communication with the abrading surface of the deviceor skin, for example: via channels through the needles or protrusions,or via channels which exit the reservoir between such needles orprotrusions, or via porous materials, or adjacent to the abradingsurface. In this embodiment, the substance or reconstituting liquid iscontained in the reservoir of the abrading device and is dispensed tothe skin surface prior to abrasion, simultaneously with abrasion, orafter abrasion. The abrading device may also include means forcontrolling the rate of delivery of the substance or reconstitutingliquid, or for controlling the amount of substance or reconstitutingliquid delivered. As an alternative, a patch, either dry orpre-moistened, may be applied to the site subsequent to abrasion tofacilitate reconstitution, or enhance introduction or uptake ofsubstances into the skin. In another aspect of the invention, the patchmay contain the medicament and may be applied to skin that waspre-treated with a microabrader device.

Nucleic acids for use in the methods of the invention may be RNA or DNA.A nucleic acid may be in any physical form suitable for topicaladministration and for uptake and expression by cells. It may becontained in a viral vector, liposome, particle, microparticle,nanoparticle, or other suitable formulation as is known in the art, orit may be delivered as a free polynucleotide such as a plasmid as isknown in the art. The nucleic acid will typically be formulated in apharmaceutically acceptable formulation such as a fluid or gel which iscompatible with the nucleic acid. Pharmaceutically acceptableformulations for use in the invention, including formulations forvaccines and allergen compositions, are also well known in the art.

It has been found that minimal abrasion (as little as one pass over theskin) is sufficient to produce an improvement in nucleic acid deliveryto skin cells. The amount of nucleic acid delivery and expressioncontinues to increase with increasing numbers of abrasive passes overthe skin. Six abrasive passes or more gave the maximum improvement innucleic acid delivery in experimental animal studies. Although allabrasive passes over the skin may be in the same direction, it ispreferred that the direction be altered during abrasion. The mostcommonly used protocol for delivery of nucleic acid vaccines today is IMinjection, usually with additional response enhancers when the dose islow. Determination of the appropriate dose of nucleic acid vaccine to bedelivered using the methods of the invention is within the ordinaryskill in the art. However, it is an advantage of certain inventivemethods that delivery of nucleic acid vaccines is more efficient than IMdelivery even without response enhancers, as evidenced by levels of geneexpression and stimulation of an immune response.

Amino acids, amino acid derivatives, peptides and polypeptides,particularly allergens and live, attenuated viruses, may also bedelivered topically according to the device and methods of theinvention. Allergens are conventionally delivered into the skin byintracutaneous puncture using devices similar to the tuberculin tinetest. However, it has been unexpectedly found that an enhancedallergenic response can be obtained by simultaneous abrasion anddelivery. This produces a more sensitive test and has the advantage thata minor or imperceptible response to the conventional allergen test maybe more easily detected using the methods of the invention. Thus, thedevices and methods of the invention result in better performance andless skin irritation and erthyma than methods using tine-based devicespreviously known in the art. Other suitable abraders for delivery ofvaccines as well as other medicaments include those disclosed in U.S.application Ser. No. 09/405,488, filed Sep. 24, 1999, and U.S.application Ser. No. 09/576,643, filed May 22, 2000, both hereinincorporated by reference, in their entirety. It will be appreciatedthat the size and shape of the surface area of the abrader, and theshape and pattern of the needles or protrusions can vary according tothe particular vaccine or other agent to be delivered and other factorssuch as ease of application and efficacy, as will be appreciated bythose of skill in the art.

Typically, to administer vaccine or other medicament using the certainmethods of the present invention, a practitioner will remove theappropriate volume from a vial sealed with a septa using a syringe, andapply the vaccine or medicament to the skin either before or followingabrasion using the microabrader. This procedure will at a minimum resultin the use of both a syringe needle and a microabrader for eachadministration procedure, and require time and attention for dosagemeasurement. Thus, it would be desirable to provide for a kit includingthe microabrader device either in combination with or adapted tointegrate therewith, the substance to be delivered.

The application of minimally invasive, microabrader devices for thedelivery of drugs and vaccines clearly present an immediate need forcoupling the device with the formulation to provide safe, efficacious,economic and consistent means for administering formulations forenabling immunogenic or other therapeutic responses. The kit provided inaccord with one aspect of the invention comprises at least onemicroabrader delivery device having an abrading surface, which mayinclude microprotrusions projecting from the abrading surface. Themicroabrader delivery device contained in the kit may be fullyintegrated, i.e. include a facet adapted to receive or integral withsaid abrading surface, a handle attachment facet, and a handle that isintegral with or detachable from said base. A reservoir containing avaccine or other medicament, and means to effect delivery may also beintegrated into the delivery device. Alternatively, the kit may containonly parts of the microabrader that may be considered disposable (forexample, the abrading surface and medicament doses), with reusable itemssuch as the handle and facet being separately supplied. Such kits may,for example, comprise multiple attachable abrading surfaces and multiplevaccine dosages suitable for mass inoculations, with handles and facetsbeing supplied separately (optionally in smaller numbers).Alternatively, the kit may contain one or more complete “one use”microabrader devices that include the abrading surface, facet, handle in“use and dispose” form. In one aspect of the invention, the kit alsocontains means for containing, measuring, and/or delivering a dosage ofa vaccine or other medicament. In another aspect of the invention, thekit also contains an effective dosage of a vaccine or other medicament,optionally contained in a reservoir that is an integral part of, or iscapable of being functionally attached to, the delivery device. Inanother aspect of the invention, the kit also contains a covering thatis an integral part of, or is capable of being functionally attached to,the delivery device. Alternatively, the vaccine or other medicament maybe supplied in a patch that is packaged in a kit also comprising anabrasion device. In this embodiment, the abrasion device is first usedto treat the skin, after which the patch is applied to the treated skinsite.

In another aspect of the invention, the kit of the invention comprises amicroabrader coated with an effective amount of the medicament orvaccine to be administered. By an “effective amount” or “effectivedosage” of a substance is intended to mean an amount that will elicit adesired response in a subject, including, but not limited to, animmunostimulatory response in the case of an allergen or vaccine, orother therapeutic or diagnostic response.

To use a kit as envisioned by certain aspects of the instant inventionthe practitioner would break a hermetic seal to provide access to themicroabrader device and optionally, the vaccine or immunogenic ortherapeutic composition. The composition may be preloaded into areservoir contained in the microabrader device or a separate applicationdevice in any suitable form, including but not limited to gel, paste,oil, emulsion, particle, nanoparticle, microparticle, suspension orliquid, or coated on the microabrader device in a suitable dosage. Thecomposition may be separately packaged within the kit package, forexample, in a reservoir, vial, tube, blister, pouch, patch or the like.One or more of the constituents of the formulation may be lyophilized,freeze-dried, spray freeze-dried, or in any other reconstitutable form.Various reconstitution media, cleansing or disinfective agents, ortopical steriliants (alcohol wipes, iodine) can further be provided ifdesired. The practitioner would then apply the formulation to the skinof the patient either before or following the abrasion step, or in thecase of a preloaded or precoated microabrader device, carry out theabrasion step without separate application of the medicament.

In one aspect of the invention, the closing patch is formed with threecomponents. The first component is skin template. The skin template is aflexible film, typically made from a plastic material, with a skincompatible adhesive layer designed to stick on the skin surface on thedistal surface of the skin template. The skin template may include acentral opening, which is pre-cut to correspond to the desired abrasionarea of the skin. The opening may also be at an edge of the skintemplate. The size of the opening corresponds to the area of the skinsurface to be abraded. In one aspect of the invention, the openinggeometry is correlated to the precise area to be abraded; wherein thearea is determined clinically from previously conducted studies on therelationship of abraded area and delivery of an effective amount of drugor vaccine. Selection of the opening size to correspond to apredetermined area allows a clinician to readily observe the area ofskin that must be abraded for effective delivery. The opening may be anyshape but is typically rectangular. In an alternate embodiment theopening is slot shaped opening. Although not critical for the invention,the skin template is typically placed onto the skin of the patient priorto the abrasion, and is affixed to the skin by the skin compatibleadhesive. The skin template may be printed with indicia to indicatedirections for use, or for proper placement locations of subsequentcoverings. The skin template assists skin pre-treatment before vaccineor drug delivery by exposing to the skin abrader the predetermined skinsurface area. Skin abrasion is performed through the opening of the skintemplate. The second component of this embodiment of the invention is anopening cover. Typically, the opening cover is formed from a pliableplastic material. Alternatively, the opening cover may be formed from asemi-rigid material to form a closed chamber when covering the window ofthe skin template. This closed chamber acts to substantially contain thedelivered volume of drug/vaccine/substance. Forming the opening cover inthe general shape of a dome may further enlarge the volume of the closedchamber, thus adding to the volume of substance that may be delivered tothe abraded area of skin.

It is desirable that the distal surface of the opening cover, whichcontacts the abraded area of the skin, should prevent absorption of drug(or vaccine) and/or adhesion of the skin to the to the opening cover. Inorder to achieve this non-binding state, the surface properties of theopening cover may be selected or treated such that they are highlyhydrophobic, at least on the distal surface. Other surface treatmentsand/or materials to prevent binding are well known in the art and couldbe used for the distal skin contact area of the opening cover.Alternatively, the distal surface of the opening cover may be coatedwith a releasable drug/vaccine formulation, which is then absorbed bythe abraded area upon contact with the abraded area. For example, thedistal surface of the opening cover may be coated with hydrogel matrixor other polymeric matrix, or as micro or nano particles coated on thedistal surface.

The third component of this embodiment of the invention is a dressingcover which is typically formed of a flexible plastic film with at leasta distal adhesive layer designed to stick both on the back of theopening cover and the skin template. The dressing cover is used afterthe abrasion/delivery process is completed. Alternatively, the dressingcover does not adhere to the opening cover and only serves to containthe opening cover between the skin template and the dressing cover.Alternatively, the dressing cover has an opening cover integrally formedonto the distal surface of the dressing cover. Thus, in this embodimentof the invention, the clinician is provided both a template for theabrasion process and a dressing to dress the abraded area after theabrasion. Alternatively, the skin template is not adhered to the skinbut is only used as a temporary guide for placement of indicia, which isprinted directly onto the patient's skin. Alternatively, the indicia areprinted directly onto the patient's skin without the use of a skintemplate. In each of the aforementioned embodiments, the indicia on thepatient's skin indicate the size of the abraded area.

Now referring to FIG. 1A, FIG. 1B and FIG. 2, shown is a patch 10 of theinvention with a skin template 100, constructed of a flexible material,having a central opening 110. Central opening 110 is sized to beslightly larger than the pre-determined abrasion area 510. Skin template100 has proximal surface 115 and distal surface 120. Distal surface 120may be coated with a skin compatible adhesive. It is desirable toconstruct skin template 100 from a clear or translucent material. Skintemplate 100 is placed onto the skin 500 with central opening 100 overthe desired abrasion area. Preferably, skin template 100 conforms to theskin 500 to which it is applied. Proximal surface 115 may containindicia with directions for use of the abrasion process, or for properplacement location of subsequent coverings. After skin template 100 hasbeen adhered to the skin 500, a microabrader is engaged to the skin 500for abrasion through central opening 110. After the abrasion process iscomplete, cover 200 is placed over opening 110. Preferably, cover 200 issized to be slightly larger than opening 110. Cover 200 may beconstructed of a clear or translucent material. As stated previously,distal surface 220 of cover 200 is, or at least the periphery of distalsurface 220 of cover 200 may be coated with adhesive so that theperiphery of distal surface 220 adheres to proximal surface 115 of skintemplate 100. Cover 200 also has proximal surface 215. Cover 200 andskin template 100 are covered by dressing 300. Dressing 300 also hasdistal surface 320. Distal surface 320 is preferably covered withadhesive, which may bond to both cover 200 and skin template 100,although distal surface 320 may only bond to skin template 100 and trapcover 200 therebetween. Proximal surface 215 of cover 200 may also bebonded to dressing 300 so that they are a single unit. It is desirablethat dressing 300 is constructed of a clear or translucent material.

Now referring to FIG. 3, which shows another aspect of the invention,dressing cover 300 is used in conjunction with a semi-rigid dome 270.The dome 270 serves to cover the abraded area 510 of the skin 500 andprevent adhesion of the skin. The dome 270 is sized such that a chamber280 is formed between the distal surface 272 of the dome 270 and theskin 500, when the patch 10 is applied. Proximal surface 275 of the dome270 may be adhered to the dressing cover 300. The material of the dome270 is a semi-rigid plastic, aluminum, other semi-pliable metal or metalfilm, or any other material compatible with the formulated activeingredient. The offset of the distal surface 272 of the chamber 280 fromthe skin 500, when the patch 10 is applied is approximately 0.1 to 0.5mm and the length and width of the chamber is slightly larger than theabraded area 510. In one aspect of the invention the chamber 270 isempty and provides a closure of the abraded/treated skin surface. Thechamber 270 protects the abraded area 510 by the cushion of empty space.The dressing cover 300 is designed to cover the abraded area 510 of skin500 after skin abrasion and application of drug or vaccine.

Now referring to FIG. 4, an alternate embodiment, chamber 280 contains adrug or vaccine formulation, which is the same as the drug or vaccinedelivered by the abrasion process. Alternatively the chamber 280contains second drug, vaccine or other bioactive substance, whichenhances delivery of the first drug or vaccine. For example, the secondsubstance may be an adjuvant or immune-stimulant that enhances deliveryof the vaccine or vaccine antigen. Alternatively, a skin abrader 400formed by a needle array is integrated into the chamber 280. The chamberis pre-filled with the drug or vaccine and sealed with a closure 600ensuring drug/device integrity and sterility.

Now referring to FIG. 5, which shows a kit of the invention. Shown aredressing 300 with its primary packaging 970, which ensures the sterilityof dressing 300. Cover 960 is used to cover the abraded area. Forexample, an expedient cover 960 may be composed of the sterile backingof a standard sterile adhesive bandage 950. Shown is the primarypackaging 900 for the sterile, adhesive bandage 950 with cover 960.

Now referring to FIG. 6, which shows an alternate embodiment of theinvention without a skin template, adhered to the skin. In thisembodiment, skin template 100 (not shown) is temporarily placed againstskin 500 and indicia 1000 is marked directly onto the skin. The skintemplate is only used as a temporary guide for placement of indicia1000, which is printed directly onto the patient's skin. Alternatively,the indicia are printed directly onto the patient's skin without the useof a skin template. The indicia 1000 on the patient's skin indicate thesize of the pre-selected abraded area or for proper placement locationsof subsequent coverings. In this figure, cover 200 is placed directlyonto the skin and protects abraded area 510. Then dressing 300 is placeonto cover 200 and the skin.

Now referring to FIG. 7A and FIG. 7B, which show another embodiment ofthe invention. In this embodiment, patch 10 is both a primary packagingfor a drug or vaccine, and delivery system to penetrate the skin afterskin disruption and also a closing patch. The primary packaging ispre-fillable with drug or vaccine formulation based on liquid or gelformulation. The drug delivery system is based on two integratedfeatures: a dressing cover 300, which is applied to the skin surfaceafter abrasion by an abrader, and a secondary delivery system. In thisembodiment, the dressing cover 300 is designed with a distal surface 320which has an adhesive designed to stick onto the skin surface. Thesecondary delivery feature is housed in chamber 280. Chamber 280 isbounded by the distal surface 272 of dome 270, and closure 600. Theperiphery 273 of the distal portion of the chamber 280 is substantiallyplaner, in order to provide a surface for closure 600 to be attached.The dressing 300 supporting the adhesive exhibits some elasticityproperty to ensure a firm contact of dome 270 onto the skin surface.Before applying the dressing cover 300 to the skin surface, closure 600is removed exposing the chamber 280. The open chamber 280 is applied tothe skin with the dressing cover 300 so that the chamber 280 is closed,now bounded by the dome 270 and the skin surface 500.

The chamber comprises three compartments: the drug reservoir 284, theswellable reservoir 282, and the aqueous reservoir 281. The drugreservoir 284 is filled with the drug to be delivered, which may be inthe form of a powder, liquid, or gel. The distal portion of the drugreservoir 284 optionally contains a microneedle array. The swellablereservoir 282 is filled with a first material, which expands in contactwith water. Typically the swellable reservoir 282 is filled with a drypolymer. Many swellable materials are known in the art, such as aDextran powder, however, any synthetic polymer actuated by humidity canbe potential candidate and could be used in the swellable reservoir 282.The aqueous reservoir 281 contains a second material, which, whenintroduced to the first material, causes an expansion in one or bothmaterials. Typically, the aqueous reservoir 281 is filled with water. Asthe co-mingled materials expand, the drug in the drug reservoir 284 isforced into the skin since the chamber is formed by the boundary of asemi-rigid, non-permeable dome 270 and permeable skin 500. Optionally,the microneedle array 400 is also forced into the skin by the expansionof the co-mingled first and second materials. Each of the threecompartments, as well as the dome and the closure could be constructedfrom aluminum, since aluminum is an approved material as primary drugpackaging; however, any suitable medical grade material can be used.Co-mingling of the first and seconds substances is accomplished byactivation of a piercing element 290 in the form of a spike or a sharppoint. To activate the device, a patient or clinician applies pressureupon the proximal portion of the dome causing piercing element 290 torupture aqueous reservoir 281 and allow co-mingling of the first andsecond substances within chamber 280, causing them to expand and forcethe drug into the skin.

In this embodiment, the use of the device is outlined in the followingsteps: prepare the skin surface by disinfecting and/or pre-treating witha microabrader; expose the adhesive on the dressing cover; remove theclosure; adhere the patch to the skin surface; activate the device,wherein the first and second material are co-mingled and start toexpand; allow patch to remain on the skin for the required period ofdrug delivery; remove the patch.

During the period of drug delivery, the drug is in direct contact withthe skin surface like a topical application, and as soon as the patch isactivated, the first material co-mingles with the second material andthe expansion of the two materials moves the drug toward the skinsurface. Optionally, the expansion also moves the microneedle arraytoward the skin surface so that the microneedle array disrupts thestratum corneum.

1. A method for delivering a substance into skin comprising the stepsof: applying a skin template onto the skin which corresponds to apredetermined abrasion area, moving an abrader across said skin toproduce an abraded area within the bounds of said predetermined abrasionarea, wherein said abrader comprises an abrading surface, and; applyingsaid substance to the abraded area.
 2. The method of claim 1 furthercomprising covering said abrasion area with a cover after said abraderis moved across said skin.
 3. The method of claim 1 wherein saidabrading surface comprises frustoconical or frustopyramidalmicroprotrusions that comprise at least one scraping edge projectingfrom said abrading surface.
 4. The method of claim 1 wherein saidsubstance is applied prior to abrasion.
 5. The method of claim 1 whereinsaid substance is applied during abrasion.
 6. The method of claim 1wherein said substance is applied following abrasion.
 7. The method ofclaim 1 wherein said microprotrusions are at least partially coated withsaid substance to be delivered.
 8. The method of claim 1 wherein saidskin template further comprises an opening.
 9. The method of claim 2wherein said cover is coated with a drug.
 10. The method of claim 2wherein said cover is coated with a vaccine.
 11. A system for deliveringa substance into skin comprising: a skin template, which is applied tothe skin, which corresponds to a predetermined abrasion area, an abraderacross said skin to produce an abraded area within the bounds of saidpredetermined abrasion area, wherein said abrader comprises an abradingsurface.
 12. The system of claim 11 further comprising a cover whereinsaid cover contacts at least a portion of said abrasion area.
 13. Thesystem of claim 11 wherein said abrading surface comprises frustoconicalor frustopyramidal microprotrusions that comprise at least one scrapingedge projecting from said abrading surface.
 14. The system of claim 11wherein said substance is applied to the predetermined abrasion area.15. The system of claim 14 wherein said substance is applied prior toabrasion.
 16. The system of claim 14 wherein said substance is appliedduring abrasion.
 17. The system of claim 14 wherein said substance isapplied following abrasion.
 18. The system of claim 14 wherein saidmicroprotrusions are at least partially coated with said substance to bedelivered.
 19. The system of claim 11 wherein said skin template furthercomprises an opening.
 20. The system of claim 12 wherein said cover iscoated a substance selected from the group consisting of drug, vaccine,and bioactive substance.
 21. The system of claim 12 wherein said coveris coated with a releasable retention means for retaining a substanceselected from the group consisting of drug, vaccine, and bioactivesubstance.
 22. A device for introducing a substance into skin of apatient through an abraded area, said device comprising: a skin dressinghaving a central depression; a substance selected from the groupconsisting of drug, vaccine, and bioactive substance; a dome coupled tosaid skin dressing and overlying said abraded area and being spaced fromsaid closure to define a cavity therebetween, and a piercing member;and, a reservoir adapted for containing at least one swellable materialand being positioned in said cavity and adapted for containing saidsubstance, said reservoir being pierceable by said piercing member anddeformable by swelling of said swellable material wherein expansion ofsaid swellable material dispenses said substance into said skin throughsaid abraded area.
 23. The device of claim 22 further comprising skinpiercing members, wherein said skin piercing members are containedwithin said reservoir and are adapted to penetrate the skin by swellingof said swellable material.
 24. The device of claim 23 wherein said skinpiercing members are at least partially coated with said substance to bedelivered.